Suryawati, S.Si, MSc, Apt.

A. Obat Primer efektifitas tinggi dengan toksisitas yang dapat diterima 1. Isoniazid 2. Rifampisin 3. Etambutol 4. Streptomisin 5. Pirazinamid B. Obat sekunder kurang efektif 1. Paraaminosalisilat 2. Sikloserin 3. Amikasin 4. Kapreomisin 5. kanamisin

Mekanisme kerja : - Efek utamanya ialah menghambat biosintesis asam mikolat (mycolic acid) yang merupakan unsur penting dinding sel mikobakterium.

Perhatikan bagian gambar yang berwarna merah: - Isoniazid menghambat biosintesis asam mikolat (mycolic acid) yang merupakan unsur penting dinding sel mikobakterium ketahanan dinding sel terganggu kematian sel

 Administration

: taken orally, intramuscularly or intravenously. Adults dosage : 5 mg/kg (46 mg/kg) daily, maximum 300 mg Contraindications : Known hypersensitivity and active, unstable hepatic disease (with jaundice) Use in pregnancy : not known to be harmful in pregnancy. Pyridoxine supplementation is recommended for all pregnant (or breastfeeding) women taking isoniazid.

Adverse effects : - hypersensitivity reactions, - sleepiness or lethargy, - peripheral neuropathy, - neurological disturbance, including optic neuritis, - toxic psychosis and generalized convulsions, Symptomatic hepatitis, - lupus-like syndrome, - pellagra, - anaemia, - arthralgias

Drug interactions Isoniazid inhibits the metabolism of certain drugs increase their plasma concentration to the point of toxicity. administering both rifampicin and isoniazid causes a reduction in plasma levels of phenytoin and diazepam.

Isoniazid increase the toxicity: - carbamazepine, benzodiazepines metabolized by oxidation (such as triazolam), - acetaminophen, - valproate, - serotonergic antidepressants, - disulfiram, - warfarin and -theophylline.

inhibits ribonucleic acid synthesis in a broad range of microbial pathogens. FK : lipid-soluble. Oral :rapidly absorbed and distributed throughout the cellular tissues and body fluids A single dose of 600 mg produces a peak serum concentration of about 10 g/ml in 24 hours, a halflife : 23 hours.

It is extensively recycled in the enterohepatic circulation, and metabolites formed by deacetylation in the liver are eventually excreted in the faeces. PK : administered in combination with other effective antimycobacterial agents (to prevent resistancy).

Administration and dosage given at least 30 minutes before meals (abs.is reduced when it is taken with food). Adults: 10 mg/kg (812 mg/kg)

Contraindications Known hypersensitivity to rifamycins. Active, unstable hepatic disease (with jaundice)

Precautions Serious immunological reactions resulting in - renal impairment, - haemolysis or thrombocytopenia (rare, RF immediately and permanently withdrawn). Clinical monitoring (and liver function tests, if possible) should be performed during treatment of all patients with pre-existing liver disease, who are at increased risk of further liver damage. Patients should be warned that treatment may cause reddish coloration of all body secretions (urine, tears, saliva, sweat, semen and sputum), and that contact lenses and clothing may be irreversibly stained.

Use in pregnancy Vitamin K should be administered at birth to the infant of a mother taking rifampicin because of the risk of postnatal haemorrhage.

 Adverse effects Gastrointestinal reactions (abdominal pain, nausea, vomiting) and pruritus with or without rash . fever, influenza-like syndrome and thrombocytopenia Exfoliative dermatitis is more frequent in HIVpositive TB patients. Temporary oliguria, dyspnoea and haemolytic anaemia Moderate rises in serum concentrations of bilirubin and transaminases,

Drug

interactions

Rifampicin induces hepatic enzymes, and may increase the dosage requirements of drugs metabolized in the liver, including: anti-infectives (including certain antiretroviral drugs discussed below and in section 5.6.1, mefloquine, azole antifungal agents, clarithromycin, erythromycin, doxycycline, atovaquone, chloramphenicol); hormone therapy, including ethinylestradiol, norethindrone, tamoxifen, levothyroxine; methadone; warfarin; cyclosporine;

 corticosteroids; anticonvulsants (including phenytoin); cardiovascular agents including digoxin (in patients with renal insufficiency), digitoxin, verapamil, nifedipine, diltiazem, propranolol, metoprorol, enalapril, losartan, quinidine, mexiletine, tocainide, propafenone; theophylline; sulfonylurea hypoglycaemics; hypolipidaemics including simvastatin and fluvastatin; nortriptyline, haloperidol, quetiapine, benzodiazepines (including diazepam, triazolam), zolpidem, buspirone.

RF reduces the effectiveness of oral contraceptives use an contraceptive pill containing a higher dose of estrogen (50 g); apply nonhormonal method of contraception throughout rifampicin treatment microbiological assays for folic acid and vitamin B12 disturbed.

Current antiretroviral drugs (non-nucleoside reverse transcriptase inhibitors and protease inhibitors) interact with rifampicin .This may result in ineffectiveness of antiretroviral drugs, ineffective treatment of TB or an increased risk of drug toxicity.

analogue of nicotinamide bactericidal against M. tuberculosis, It is highly effective during the first 2 months of treatment while acute inflammatory changes persist. FK readily absorbed from the gastrointestinal tract and is rapidly distributed throughout all tissues and fluids. Peak plasma concentrations: attained in 2 hours T : about 10 hours. Metabolized in the liver and excreted in the urine.

Administration and dosage Pyrazinamide is administered orally. Adults (usually for the first 2 or 3 months of TB treatment): 25 mg/kg (2030 mg/kg) daily
Contraindications Known hypersensitivity. Active, unstable hepatic disease (with jaundice)

 Precautions
Patients

with diabetes should be carefully monitored since blood glucose concentrations may become labile. Gout may be exacerbated. Clinical monitoring (and liver function tests, if possible) should be performed during treatment of patients with pre-existing liver disease. In patients with renal failure, pyrazinamide should be administered three times per week, rather than daily

 Use

in pregnancy The 6-month regimen based upon isoniazid, rifampicin and pyrazinamide should be used whenever possible. Although detailed teratogenicity data are not available, pyrazinamide can probably be used safely during pregnancy.

 Adverse

effects gastrointestinal intolerance. Hypersensitivity reactions Moderate rises in serum transaminase Severe hepatotoxicity is rare. Hyperuricaemia Gout Arthralgia anaemia photosensitive dermatitis.

 derived

from Streptomyces griseus Used for TB and treatment of sensitive Gram-negative infections. FK not absorbed from the GI tract given intramuscularly T : 23 hours, excreted unchanged in the urine.

Administration and dosage administered by deep intramuscular injection and intravenous administration. Dose : 15 mg/kg (1218 mg/kg) daily, maximum daily dose is 1000 mg. Patients aged over 60 years may not be able to tolerate more than 500750 mg daily reduce the dose to 10 mg/kg per day for patients in this age group. Patients weighing less than 50 kg may not tolerate doses above 500750 mg daily.1 Contraindications Known hypersensitivity. Auditory nerve impairment. Myasthenia gravis. Pregnancy.

Precautions Hypersensitivity (rare, during the first weeks of treatment), nephrotoxicity and ototoxicity. The dose should be maintained at 1215 mg/kg but at a reduced frequency of 23 times per week serum levels should be monitored periodically Use in pregnancy not be used in pregnancy (cause auditory nerve impairment and nephrotoxicity in the fetus).

Adverse effects Rash at injection sites. Numbness and tingling around the mouth Cutaneous hypersensitivity Impairment of vestibular function (uncommon) damage to the 8th cranial (auditory) nerve include ringing in the ears, ataxia, vertigo and deafness ( in the first 2 months of treatment and is reversible if the dosage is reduced or the drug is stopped ). Nephrotoxic Haemolytic anaemia, aplastic anaemia, agranulocytosis, thrombocytopenia and lupoid reactions(rare).

Drug interactions Other ototoxic or nephrotoxic drugs should not be administered to patients receiving streptomycin. These include other aminoglycoside antibiotics, amphotericin B, cefalosporins, etacrynic acid, cyclosporin, cisplatin, furosemide and vancomycin. Streptomycin may potentiate the effect of neuromuscular blocking agents administered during anaesthesia.

 active

against M. tuberculosis, M. bovis and some nonspecific mycobacteria. FK absorbed from GI tract Plasma concentrations peak in 24 hours and t1/2: 34 hours. excreted in the urine both unchanged and as inactive hepatic metabolites. About 20% is excreted unchanged in the faeces.

Administration and dosage administered orally. Adults doses: 15 mg/kg (1520 mg/kg) daily
Dosage must always be carefully calculated on a weight basis to avoid toxicity, and the dose or the dosing interval should be adjusted in patients with impaired renal function (creatinine clearance <70 ml/min). If creatinine clearance is less than 30 ml/minute, ethambutol should be administered 3 times per week. Contraindications Known hypersensitivity. Pre-existing optic neuritis from any cause.

Precautions discontinue treatment when sight or perception of colour deteriorates. Plasma ethambutol concentration should be monitored if creatinine clearance is less than 30 ml/min. Use in pregnancy Ethambutol is not known to be harmful in pregnancy.

Adverse effects Dose-dependent optic neuritis impairment of visual acuity and colour vision Signs of peripheral neuritis in the legs. Other rare adverse events include generalized cutaneous reaction, arthralgia and, very rarely, hepatitis.

 co-trimoxazole

preventive given throughout

TB treatment. co-trimoxazole is known to prevent Pneumocystis jirovecii and malaria and have an impact on a range of bacterial infections in HIV-positive TB patients.

Antiretroviral therapy improves survival in HIVpositive patients TB treatment should be started first, followed by ART within the first 8 weeks of starting TB treatment WHO recommends: the first-line ART regimen contain two nucleoside reverse transcriptase inhibitors (NRTIs) plus one non-nucleoside reverse transcriptase inhibitor (NNRTI) . The preferred NRTI: zidovudine (AZT) or tenofovir disoproxil fumarate (TDF), combined with either lamivudine (3TC) or emtricitabine (FTC). For the NNRTI: either efavirenz (EFV) or nevirapine (NVP)

 For

those who are unable to tolerate EFV or who have contraindications to an EFV-based regimen, may use: - AZT +3TC + NVP or - TDF +3TC or FTC + NVP or - a triple NRTI regimen (AZT+3TC+ABC or AZT+3TC+TDF) (see: http://www.who.int/hiv/pub guidelines/en)

1.
2. 3. 4. 5. 6.

Bronkodilator (Adrenergik dan antikolinergik, derivat xantin) Kortikosteroid Mukolitik dan ekspektoransia Antihistamin Zat antileukotrien Antialergi :kromoglikat, nedocromil, ketotifen, oksatomida

 Nama

Obat : salbutamol, terbutalin, tetroquinol, fenoterol, rimiterol, prokaterol, klenbuterol, salmeterol dan formeterol. Mek kerja: stimulasi reseptor 2 di trakea (batang tenggorok) dan bronchi aktivasi adenil siklase pe (+) cAMP bronkodilatasi & pe pelepasan histamin Penggunaan: melawan serangan atau pemeliharaan dengan kombinasi bersama kortikosteroid dan kromoglikat

 Short

acting agents - Durasi aksi :4-6 jam - Obat dengan selektifitas beta-2 lebih besar : albuterol, levalbuterol, bitolterol, pirbuterol dan terbutalin - Obat dengan selektifitas beta-2 lebih kecil : isoproterenol, metaproterenol dan isoetarin Long acting agents - Durasi aksi :12 jam - Contoh obat: Formoterol

Nama Obat Salbutamol

Dosis 3-4 dd 2-4 mg (sulfat), inhalasi 3-4 dd 2 semprotan dari 100 mcg Akut: 2 puff, diulang stlh 15 menit Serangan hebat: im/sc 250500 mcg diulang ssdh 4 jam 2-3 dd2,5 mg (sulfat), inhalasi 3-4 dd 1-2 semprotan dr 250 mcg, maks 16 puff sehari, sc 250 mcg, maks 4x sehari 3 dd 2,5-5 mg (bromida), supp 15 mg, inh 3-4 dd 1-2 semprotan dr 200mcg 2-4 dd 3 mg(klorida), sc. 0,10,2 mg, iv 50-100 mcg Oral 2 dd 50 mcg Inh. Maks 4 dd 2 semprotan dr

Catatan -ES : jarang - aman utk kehamilan & laktasi

Terbutalin

- aman utk kehamilan & laktasi - &2 selektif

Fenoterol

Tretoquinol Prokaterol Rimiterol

 Bekerja

dengan memblok asetilkolin pe (-) cGMP bronkodilatasi (efek tidak sekuat beta agonis dan teofilin) FK : tidak diserap tidak ada efek sistemik. Kadar maks: 1-2 jam dan bertahan 3-5 jam. Onset (15-20 menit) Sediaan: 20 g/semprotan Dosis : 2 inhalasi/3-4 jam (maks. 12 inhalasi/24 jam)

 Keuntungan

: dosis rendah dengan efek samping kecil Dilakukan pada saat perkembangan penyakit dan gejala memburuk Contoh : kombinasi albuterol dan ipratropium

 MK

: inhibisi fosfodiesterase pe (+) kadar cAMP inhibisi pelepasan mediator dari sel mast dan leukosit bronkodilatasi PK : terapi pemeliharaan PPOK ES : dispepsia, mual, muntah, diare, sakit kepala, pusing, takikardia Dosis : 2 x sehari 200 mg, ditingkatkan bertahap setiap 3 hingga 5 hari Sediaan : microfine retard (sediaan lepas lambat) memelihara kadar obat lebih konsisten

 MK

: mengikat reseptor steroid di sitoplasma mempengaruhi sintesa protein di dalam inti sel efek Efek : mencegah atau menekan timbulnya gejala inflamasi (menghambat udem, deposit fibrin, dilatasi kapiler, dsb) FK : abs oral baik ES : gangguan cairan dan elektrolit, hiperglikemia, daya tahan tubuh rendah, osteoporosis, dll Sediaan : oral, aerosol

 PK

: terapi paliatif pada asma dan copd bersama bronkodilator Digunakan pada pasien pada penyakit tingkat III atau IV (FEV1 kurang dari 50%)

Penggunaannya pada bronkhitis dilakukan jika 2 dari 3 gejala berikut tampak: pe (+) dispnea, pe (+) volume sputum dan kandungan nanah sputum Pemilihan AB: didasarkan pada organisme yg paling sering yaitu : Haemophilus influenza, Moraxella catarrhalis, Streptococcus pneumonia dan Haemophilus parainfluenza Rekomendasi AB : makrolida (azitromisin dan klaritromisin), sefalosporin gen-2 (sefaklor) atau 3 (sefotaksim)atau doksisiklin, fluorokinolon (levofloksasin, gatifloksasin, moksifloksasin)

 Lihat

kuliah farmakologi blok 5 : alergi, imunologi dan infeksi

 MK

: menghambat pelepasan histamin alergi FK : abs di sal. Cerna, eks lewat urin & tinja (utuh & metabolit) ES : Sedasi, Vertigo, tinitus, penglihatan kabur, mual atau muntah, Mulut kering, Demam, Aritmia jantung, me (+) nafsu makan dan berat badan, me (-) jml trombosit (bila (+) antidiabetik oral) PK : profilaksis asma bronkial Sediaan : tab 1 mg, sirup 0,2 mg/ml Dosis : 2 x 1,38-2,76 mg (dewasa)

Mek. Kerja: bekerja terhadap mast cell menghambat pelepasan mediator inflamasi spt: histamin, serotonin dan leukotrien PK : mencegah serangan asma dan bronkitis alergi FK : 5-10% mencapai bronki, t1/2 =1,5-2 jam, durasi: 6 jam ES: rangsangan lokal pd selaput lendir tenggorok dan trakea (batuk, kejang bronki) Kehamilan : aman Dosis: inhalasi 4 dd 1 puff (20 mg), nasal 4 dd 10 mg serbuk, mata: 4-6 dd 1-2 tetes dr larutan 2%

 Merupakan

alkaloid opium yang menghambat refleks batuk MK : bekerja pada reseptor opioid (, k, ) di SSP efek FD : analgesia, mual, muntah, depresi nafas, dilatasi pupil mata, menghambat sekresi HCl, memperlambat pencernaan makanan di usus halus, dilatasi pembuluh darah kulit, pe (-) suhu badan. PK : batuk dan sesak

 Tidak

berefek anagetik dan adiktif Sediaan: tablet 10 mg dan sirup 15 mg/5 ml Dosis dewasa: 10-30 mg diberikan 3-4 kali sehari

 Obat

lokal yang dapat mengencerkan sekret saluran nafas dengan jalan memecah benangbenang mukoprotein dan mukopolisakarida dari sputum ES : mual dan pe(+) transaminase serum Dosis oral dewasa : 3x 4-8 mg/hari
Mukolitik

lain : Ambroksol dan asetil sistein

 Obat

lokal yang dapat merangsang pengeluaran dahak (perangsangan N.vagus) Dosis dewasa Amm. Klorida : 300 mg/5 ml tiap 2-4 jam Dosis dewasa GG : 2-4 kali 200-400 mg sehari